Lawrence Fleckenstein

Assessment of the biologic availability of digoxin in man.

Low serum digoxin levels were found in 8 institutionalized patients with congestive heart failure despite daily administration, in standard dosage, of a digoxin preparation for 4 weeks. All 8 patients developed serum levels within the accepted therapeutic range after receiving another digoxin preparation for 1 week. Analysis revealed that the first preparation did not meet USP reqUirements of content uniformity. In vitro testing demonstrated marked differences in dissolution characteristics between preparations. Large differences in the extent of availability were demonstrated in a single‐dose crossover study in 5 healthy volunteers. It was established that the pharmacokinetic data obtained from cumulative urinary excretion reflected differences in the area under the 8 hour serum digoxin curve during single‐dose studies and the postdistribution serum concentrations in multiple‐dose studies. Single‐dose studies with urine collections for 24 hours seem adequate to assess differences between formulations of digoxin tablets affecting biological availability and to develop correlation with in vitro dissolution tests.

Pharmacokinetics of an extended‐dose halofantrine regimen in patients with malaria and in healthy volunteers

The pharmacokinetics and tolerance of a 4.5 gm 7‐day halofantrine loading dose regimen were evaluated in 10 Thai patients with malaria and in 10 noninfected volunteers. Halofantrine peak plasma concentrations and bioavailability on the first day of treatment were significantly lower in patients with malaria than in healthy volunteers. Halofantrine elimination half‐life was significantly shorter in patients with malaria than healthy control subjects (9.5 versus 15.8 days). These data show a distinct effect of acute malaria on the absorption and elimination of the drug. In addition, marked intersubject and intrasubject variability in peak and trough halofantrine levels was observed, indicating variable drug absorption. This dosing regimen was effective and well tolerated, with mild transient diarrhea during the first few days of treatment in both groups. To produce consistently effective drug levels, the currently recommended dosing regimens may be suboptimal. Slow halofantrine elimination raises concern for induction of parasite resistance when the drug is used in endemic areas of the world.

Sodium salicylamide: Relative bioavailability and subjective effects

The bioavailability of sodium salicylamide (NaSAM) in solution of salicylamide (SAM) tablets was compared in 6 healthy human volunteers. Bioavailability was assessed by plasma level determinations of nonmetabolized salicylamide (free SAM) and salicylamide plus conjugated metabolites (total SAM) for 3 hr following oral doses of 0.65, 1.30, 1.95, and 2.60 gm of salicylamide. The availability of NaSAM was found to be superior to SAM and dose‐dependent. Mean peak levels offree SAM and total SAM were higher and were reached earlier after NaSAM liquid than after SAM tablets. Significantly higher mean levels offree SAM were found at the 1.95 and 2.60 gm dose levels after NaSAM administration than after SAM. Mean total SAM concentration was significantly higher after NaSAM at all dosage levels. The sedative effects of salicylamide were assessed with a self‐scoring questionnaire. Sedation seemed to increase with increasing dose of both NaSAM and SAM. The sedative response occurred earlier after NaSAM than after SAM. Side effects were minor and transient in nature, occurred at the higher dosage levels, and were predominantly lightheadedness and dizziness. Because NaSAM produces higher drug levels and has a more rapid onset of subjective effects, we conclude that it represents a potentially superior dosage form.

Correlation between electrocardiographic changes, serum digoxin, and total body digoxin content

Serial electrocardiograms and serum digoxin levels were obtained in four healthy volunteers receiving daily doses of digoxin, 0.25 mg for the first two weeks and 0.5 mg for two more weeks. We found a linear relationship between serum digoxin levels and the “PTQ index” (a function of the PR‐interval, corrected QT‐time, and T‐wave depression). In 3 of the 4 subjects the correlation was statistically significant. The degree of linear correlation was improved when PTQ was correlated with the computer‐calculated total body burden of digoxin.